Endocrine therapy remains a major adjuvant treatment for estrogen receptor (ER)-positive breast cancer, yet its clinical efficacy is frequently compromised by primary or acquired resistance, leading to tumor recurrence and poor prognosis. In this study, we identified RSK2 (p90 ribosomal S6 kinase 2) as a critical mediator of endocrine resistance in ER-positive breast cancer. Analysis of publicly available datasets and our clinical samples revealed that high expression of RSK2 is associated with unfavorable outcomes in patients treated with endocrine therapy. RSK2 overexpression confers resistance to both tamoxifen and fulvestrant, two commonly used ER antagonists. We show that RSK2 is upregulated in tamoxifen-resistant breast cancer cells compared to parental controls, and that RSK2 knockdown restores tamoxifen sensitivity and inhibits tumor progression in vitro and in vivo . Further, we found that RSK2 stabilizes c-Myc by phosphorylating it at serine 62, thereby enhancing the transcriptional of ERBB4, which in turn promotes ER-driven proliferation. Moreover, positive correlations between RSK2, c-Myc and ERBB4 were observed in ER-positive breast cancer specimens from patients. Notably, by screening the FDA-approved drug library, we identified emetine, an anti-protozoan drug used in the treatment of ameobiasis, as a potential RSK2 degrader and a modulator of tamoxifen resistance in preclinical models. Together, these findings establish the RSK2–c-Myc–ERBB4 axis as a therapeutic vulnerability in endocrine resistant breast cancer, and propose the repurposing of emetine as a sensitizer of endocrine therapy for breast cancer. RSK2 drives endocrine resistance in ER + breast cancer by stabilizing c-Myc and enhancing ERBB4 transcription. Emetine, an FDA-approved agent, degrades RSK2 and reverses tamoxifen resistance, offering a repurposed therapeutic strategy.
Jiang et al. (Fri,) studied this question.